Heparin is a sulphate-containing polysaccaride, which on a large scale is isolated from intestinal mucus from swine or lung from cattle. It is used as an anti-coagulant medicament. Low molecular weight heparin is obtained by depolymerisation of heparin, normally with a molecular weight of 2000 to 9000 Da. Low molecular weight heparins are clinically used as anti-thrombotic agents.
Fragmin.RTM. is a low molecular weight heparin, which has been on the market since 1985 and is manufactured by Pharmacia & Upjohn. It is an antithrombotic agent useful in the treatment and prophylaxis of thrombosis, containing dalteparin sodium with an average molecular weight of 5000 Da. Dalteparin sodium is produced through nitrous acid depolymerisation of sodium heparin from porcine intestinal mucosa. It is composed of strongly acidic sulphatcd polysaccaride chains with an average molecular weight of 4000-6000 and about 90% of the material within the range 2000-9000 Da.
Other low molecular weight heparins on the market are e.g. Klexane.RTM. (enoxaparin). Fraxiparine.RTM. (nadroparin), Clivarin.RTM. (reviparin) and Innohelp.RTM. (tinzaparin). Different uses within the therapeutic area have been suggested for low molecular weight heparin such as treatment of diabetic nephopathy and diabetic neuropathy (EP513513), treatment of chronical renal insufficiency (EP710483), inhibition of TNF-.alpha. secretion (WO9219249) and treatment of inflammatory or immunological diseases (WO9418988). During the past tell years considerable progress has been made in the medical treatment of patients with acute myocardial infarction as well as unstable and stable angina pectoris. In this type of patients with coronary artery disease the risk of total occlusion and development of a larger myocardial infarction can be reduced by 50% by aspirin (1, 2, 3) and by another 65% by heparin infusion or weight-adjusted s.c. dalteparin, a low molecular weight heparin, for six days (1, 2, 4, 5), reducing the myocardial infarction rate to 1-2% during this period During the short-term dalteparin/heparin treatment, symptoms subside (2, 5) but a significant stenosis often remains in the artery because of the pre-existing atherosclerotic lesion and/or remaining thrombotic material (6-8). Still, after the acute treatment period the risk of a new myocardial infarction is around 10% after six weeks and 15% after six months, despite conventional treatment. Therefore, a long-term pharmaceutical and/or interventional policy is urgently needed in these patients to reduce the long-term event rate.
The FRISC study (5) demonstrated that treatment with a low molecular weight (l.m.w.) heparin (dalteparin, Fragmin.RTM.) influenced the risk of death/myocardial infarction. It was shown that Fragmin.RTM. 120 IU/kg/12 h for six days compared to placebo reduced myocardial infarction by 63%, recurrent angina and the need for urgent revascularisation by 50% during the initial six days. During the continued long-term treatment using 7,500 IU/24 h for forty days or corresponding placebo the absolute reduction in event rates was maintained.
However, early after the lowering of the dose at six days there were indications of reactivation of the disease.
Numerous studies have demonstrated that signs of ischemia at ambulatory monitoring or stress tests might identify patients at an increased risk of subsequent cardiac events (9-14).
Most of these studies were performed without the use of modern medication, such as aspirin, .beta.-blockers, ACE-inhibitors and lipid lowering drugs. At the present time the utilisation and timing of revascularisation in these patients is variable and very little guidance can be obtained from the presently available scientific reports. Inadequate use of modern protective medication and invasive procedures might result in considerable consequences both for the patients and the costs of medical care. Therefore, it seemed essential to explore further the protective effects of prolonged intense antithrombotic medication. Of equal interest has been to elucidate whether a direct invasive approach with early coronary revascularisation had any advantages compared to a stepwise selective approach with invasive procedures only at recurring or incapacitating symptoms or ischemia in patients with unstable coronary artery disease, who received optimal protective medication.
ABBREVIATIONS AND DEFINITION OF TERMS ACE angiotensin converting enzyme Angiography Study of vessels Anti-ischemic drugs defined as .beta.-blockers, nitrates (long- and short-acting), calcium antagonists ASA aspirin, acetyl salicylic acid BMI body mass index CABG coronary artery bypass grafting CAD coronary artery disease Lipid lowering drugs defined as statins, fibrates and other lipid lowering drugs l.m.w. heparin low molecular weight heparin MI myocardial infarction Other cardiovascular drugs defined as ACE-inhibitors, digitalis, diuretics drugs p.o. per oral PTCA percutaneous transluminal coronary angioplasty p-value Cochran-Mantel-Haenszel test Revascularisation, Rev restoration of blood supply by surgical intervention e.g. balloons and/or by-pass s.c. subcutaneous Non-invasive policy = stepwise selective approach with coronary angiography and coronary revascularisation only at recurring br incapacitating symptoms or severe ischemia at exercise test Invasive policy = direct invasive approach with early coronary angiography and revascularisation FIGS. FIG. 1 Probability of death or MI during treatment up to 3 months FIG. 2 Death, MI or revascularisation (comulative hazard) FIG. 3 Death or MI (comulative hazard)